The general aim of the program is to identify changes in the opioid peptide systems that are characteristic of opiate (heroin) dependence. The five- year program described here is concentrated on one of the three opioid peptide genes, prodynorphin. Pre-clinical evidence suggests that dynorphins are involved in opiate tolerance, dependence and withdrawal. Studies will be conducted in two general phases: 1. pre-clinical phase in which we will continue our studies of the mechanisms of tolerance and dependence using animal models and tissues and/or isolated cells of human origin and 2. clinical phase in which we will apply knowledge obtained in the pre- clinical phase to observe and measure indices of dynorphin activity during specific stages of the human addiction cycle and during electrostimulation procedures that have been reported to increase endogenous opioid activity. Naturally, as in any long-range proposal, the studies performed in years three to five may be different depending on findings in the earlier years.